After the results of a clinical trial indicated the need for improved methods of drug delivery and distribution is solid tumors, new approaches to transfer genetic material into tumor and normal central nervous system (CNS) tissue are being explored. Normal CNS structures, tumors, normal and tumor vasculature, and choroid plexus epithelium are being targeted. New viral vectors, including adenoviruses, are being evaluated for potential therapeutic approaches. W are investigating techniques to enhance the delivery of genetic vectors to the CNS and to CNS tumors via intracarotid infusion after temporarily opening the blood-brain barrier using hyperosmolar agents such as mannitol or nitric oxide donors, which have been shown to selectively open the blood-tumor barrier to small molecules. The results indicate that this approach might be an effective new way of opening the blood-brain barrier in patients with brain tumors to enhance delivery and distribution of genetic vectors. In addition, a method to quantify gene delivery to the brain and to tumors is being developed. Using a radiolabeled adenoviral vector, we are studying the distribution of the viral vector in normal brain tissue and tumors using quantitative autoradiography (QAR) and modern image analysis techniques. With this approach, it should be possible to develop a method to monitor the distribution of genetic material in patients with brain tumors using positron emission tomography (PET).